Animal models based on genetic manipulations can contribute enormously to our understanding of diseases of the brain. Mutant mice with reduced expression of the Sp4 transcription factor display deficits in sensorimotor gating and contextual learning that resemble putative endophenotypes for schizophrenia. The Sp4 gene is significantly associated with schizophrenia and bipolar disorder. In mouse studies, reduced expression of the Sp4 gene impaired long-term potentiation (LTP) in hippocampal CA1, impaired spatial learning, and markedly decreased the expression of NMDAR1, the core subunit for NMDA glutamate receptors. Impaired NMDA function plays a central role in the pathophysiology of schizophrenia. This identification of a novel Sp4-NMDAR1 pathway provides a basis for cross-species studies related to human psychiatric disorders. This renewal application investigates how Sp4 regulates expression of NMDAR1 proteins to modulate neural pathways involved in sensorimotor gating and cognitive functions. The central hypotheses are that Sp4 post-transcriptionally regulates the expression of NMDAR1 and that restoration of Sp4-NMDAR1 expression in specific brain regions will reverse both sensorimotor gating and cognitive deficits in Sp4 hypomorphic mice. Four Specific Aims will test these hypotheses: Aim 1: To elucidate molecular mechanisms for differential expression of NMDAR1 proteins between wildtype and Sp4 hypomorphic mice. The localization of NMDAR1 mRNA will be examined by in situ hybridization. The differential translation and turnover of NMDAR1 proteins will be examined using TimeSTAMP2.2-Venus tag. Aim 2: To reverse deficient sensorimotor gating by restoring Sp4-NMDAR1 expression in excitatory and inhibitory neurons respectively. The expression of Sp4-NMDAR1 will be restored in excitatory and inhibitory neurons of both neocortex and hippocampus, to reverse prepulse inhibition gating deficits in Sp4 hypomorphic mice. Molecular and pharmacological studies will further characterize the conditional rescued mice. Aim 3: To determine whether Sp4 hypomorphic mice exhibit cognitive deficits modulated by the frontal cortex, and whether restoration of Sp4-NR1 expression in frontal cortex will reverse these deficits. Both the Attentional-Set-Shifting Task and the Odor Span Task will be used to examine cognitive functions in Sp4 hypomorphic and conditional rescued mice. Aim 4: To test whether restoration of Sp4 expression in hippocampal CA1 is sufficient to reverse the LTP and spatial learning deficits in Sp4 hypomorphs. Sp4- NMDAR1 expression will be restored in CA1 by crossing CamK2a-Cre and Sp4 hypomorphic mice. The formation and consolidation of spatial and contextual memories will be examined in the Sp4 hypomorphic mice harboring CamK2a-Cre. The proposed studies will help elucidate molecular mechanisms underlying the modulation of sensorimotor gating and learning, and aid the development of clinical interventions to prevent the down-regulation of Sp4-NMDAR1 pathway in human psychiatric disorders. PUBLIC HEALTH RELEVANCE: The Sp4 gene, which has recently been associated with both schizophrenia and bipolar disorder, codes for an important transcription factor in brain cells that regulates the function of glutamatergic receptors involved in the cognitive impairments in psychiatric disorders. This project seeks to use animal models to elucidate molecular mechanisms related to specific cognitive abnormalities in schizophrenia, in order to aid the development of clinical interventions to prevent the dysregulation of the Sp4-glutamate pathway in human psychiatric disorders.